Abstract

Homeostatic systems that rely on genetic regulatory networks are intrinsically limited by the transcriptional response time, which may restrict a cell’s ability to adapt to unanticipated environmental challenges. To bypass this limitation, cells have evolved mechanisms whereby exposure to mild stress increases their resistance to subsequent threats. However, the mechanisms responsible for such adaptive homeostasis remain largely unknown. Here, we used live-cell imaging and microfluidics to investigate the adaptive response of budding yeast to temporally controlled H2O2 stress patterns. We demonstrate that acquisition of tolerance is a systems-level property resulting from nonlinearity of H2O2 scavenging by peroxiredoxins and our study reveals that this regulatory scheme induces a striking hormetic effect of extracellular H2O2 stress on replicative longevity. Our study thus provides a novel quantitative framework bridging the molecular architecture of a cellular homeostatic system to the emergence of nonintuitive adaptive properties.Harmful external conditions, such as extreme heat or radiation, can cause stress to cells that may lead to permanent damage and even death. Cell stress is responsible for some cancers and degenerative diseases, and is involved in the process of aging. Cells respond to stress by modifying their activities in order to prevent damage from occurring. Some studies have suggested that the ability of cells to survive a stressful situation might depend both on the severity of the stress and also on the way in which the stress is applied. For example, the stress might start suddenly or develop more gradually.Cells exposed to a mild level of stress develop a tolerance that enables them to survive stronger doses of the same stress in the future. However, it is not clear how cells acquire such tolerance, and whether mild levels of stress can have more general benefits to cells, such as increased lifespan.Hydrogen peroxide and other “oxidative” compounds play important roles in cells, but they are also capable of causing damage so their levels must be tightly controlled. Goulev et al. developed a “microfluidic” device to study the effects of oxidative stress on yeast cells. The device made it possible to precisely control the level of hydrogen peroxide in the cells’ environment while monitoring the cells’ stress responses.The experiments show that exposing yeast cells to gradually increasing levels of hydrogen peroxide can train the cells to be able to survive when they are exposed to high levels of this compound. This ability depends on the activity of specific enzymes called peroxidases that are known to be able to destroy hydrogen peroxide inside the cells. The experiments suggest that gradually increasing levels of hydrogen peroxide trigger increases in the production of peroxidases that protect the cells against future oxidative stress.Further experiments show that even a very low dose of hydrogen peroxide is sufficient to activate the production of the enzymes, leading to an increase in the lifespan of the cells. A future challenge will be to investigate whether the principles identified in this work also apply to other stress responses in yeast.